Nuclear factor of activated T cells (hereinafter, singly referred to as NFAT) was discovered as a factor that activates transcription of Interleukin-2 (IL-2), which is important for the activation of T cells, and it has been reported that the transcriptional activity of the NFAT is regulated by a serine/threonine phosphatase, calcineurin, which is a target of immunosuppressants such as cyclosporine A (hereinafter, simply referred to as CsA) and tacrolimus (hereinafter, simply referred to as FK506) (see FIG. 5). That is, CsA or FK506 suppresses T cell activation by inhibiting the NFAT signal, CsA or FK506 has been approved not only as a transplant immunosuppressant but also as a therapeutic drug for rheumatoid arthritis, psoriasis and atopic dermatitis, which are known to be involved in the immune system. The system in which when such an NFAT binds to an NFAT-binding sequence (“NFAT site” in FIG. 2), transcription of genes downstream of the NFAT-binding sequence is promoted, is referred to as “NFAT signal.”
On the other hand, it has been reported that a hair-growing (including hair regrowth) effect can be expected by inhibiting the NFAT signal (Non-Patent Document 1). It has been also reported that a derivative of CsA which inhibits the NFAT signal can be used as a hair-growing agent (Patent Documents 1 and 2).
Here, in the treatment of alopecia such as male pattern baldness and alopecia areata, drugs such as a blood circulation stimulant, an immunosuppressant, a metabolic stimulant, a vitamin preparation and an antiandrogenic preparation have been hitherto used experientially as hair-growing agents. However, in many cases, these drugs show varying effects depending on the symptoms or physical constitution, so that the effects of the drugs are not yet satisfactory. Furthermore, when used in large amounts, the drugs may cause unpleasant irritant odor sensation at the site of application of the drugs, or may cause dermatitis upon continued use. In a significant number of alopecia cases such as male pattern baldness and alopecia areata, the details of the mechanism of pathogenesis is not yet clearly known, and it is the current situation that a search for suitable hair-growing agents is being conducted.
Furthermore, NFAT not only has an action on hair growth or an action on the immune system, but is also expressed in many organs and has been recognized as a “multifunctional transcription factor” that fulfills critical roles, for example, formation of muscular tissues due to the regulation of heart muscle and skeletal muscle differentiation, formation of a neural network in the brain, bone metabolism due to the regulation of osteoblastic differentiation, and the like.
The role of NFAT signal that affects the living body is as discussed above, but it has been reported that when the NFAT signal is inhibited, an immunosuppressive action (Non-Patent Document 2), treatment of psoriasis (Non-Patent Document 3), treatment of atopic dermatitis (Non-Patent Document 4), suppression of (heart) muscle hypertrophy (Non-Patent Document 5), a potential of an anti-rheumatic drug (Non-Patent Document 6), a suppressive action on osteoclastic differentiation (Non-Patent Document 7), and the like can be expected.
Furthermore, since NFAT is mediated by a pathway to produce immune cytokine, IL-2, as described above, an NFAT signal inhibitor is useful for the treatment or prevention of diseases that are considered to involve immune cytokines, including autoimmune diseases.
Examples of such target diseases include various cancers, various leukemias, various hepatitides, various infections, systemic lupus erythematosus, inflammatory bowel diseases (ulcerative colitis, Crohn's disease), multiple sclerosis, insulin-dependent diabetes, peptic ulcer, septic shock, tuberculosis, infertility, arteriosclerosis, Behcet's disease, asthma, nephritis, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia, chronic pancreatitis, peripheral vascular diseases, sepsis, interstitial liver diseases, situational ileitis, and multiple sclerosis.
Therefore, when a new NFAT signal inhibitor is identified, uses thereof as an immunosuppressant, a therapeutic agent for psoriasis, a therapeutic agent for atopic dermatitis, a suppressant for (heart) muscle hypertrophy, an anti-rheumatic drug, and a therapeutic drug for bone metabolic diseases, and novel medicinal uses such as listed above, are expected. Furthermore, when a new NFAT signal inhibitor is identified, uses thereof as a quasi-drug such as a hair-growing agent or a hair growth promoting agent, and cosmetic uses are expected.
Meanwhile, there have been reports that extracts of plants belonging to the genus Angelica are recognized to have a hair-growing, hair regrowth, or hair-nourishing effect (Patent Documents 3 to 6). Specifically, Patent Document 3 discloses a hair-nourishing agent, hair-growing agent containing a Dong Quai (Angelica sinensis) extract. Patent Document 4 discloses a hair-nourishing agent containing an essential oil of Angelica glauca. Patent Document 5 discloses a hair regrowth and hair growth promoting material containing an extract of Bai Zhi (Angelica dahurica Benth. Et Hook.). Patent Document 6 discloses a hair beautifying material such as a hair-growing and hair-nourishing agent, containing an extract of Ashitaba (Angelica keiskei koidz).
Furthermore, in regard to the components contained in Angelica plants, reference can be made to Non-Patent Documents 8 and 9, and it is shown that an extract of American angelica contains linear type furanocoumarins such as imperatorin and xanthotoxin, or angular type furanocoumarins such as angelicin. It is also described in Non-Patent Document 10 that linear type furanocoumarins such as imperatorin have an NFAT signal inhibitory action, but it has not been known that the angular type furanocoumarins according to the present invention are involved in the NFAT signal or in the hair-growing, hair regrowth or hair-nourishing effects.
At present, examples of compounds that are known to have an NFAT signal inhibitory activity include, in addition to those described above, apigenin (Non-Patent Document 11) and rosemaric acid (Non-Patent Document 12), which are contained in various edible plants, and examples of compounds that are known to have an NFAT signal enhancing activity include genistein (Non-Patent Document 13).